An attenuated vaccine (or a live attenuated vaccine, LAV) is a

vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.

created by reducing the

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

of a

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the virus (

inactivated vaccine An inactivated vaccine (or killed vaccine) is a vaccine consisting of virus particles, bacteria, or other pathogens that have been grown in culture and then killed to destroy disease-producing capacity. In contrast, live vaccines use pathogens ...

). Attenuated vaccines stimulate a strong and effective immune response that is long-lasting. In comparison to inactivated vaccines, attenuated vaccines produce a stronger and more durable immune response with a quick immunity onset. Attenuated vaccines function by encouraging the body to create antibodies and memory immune cells in response to the specific pathogen which the vaccine protects against. Common examples of live attenuated vaccines are measles, mumps, rubella,

yellow fever Yellow fever is a viral disease of typically short duration. In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains – particularly in the back – and headaches. Symptoms typically improve within five days. ...

, and some influenza vaccines.

Development

Attenuated viruses

Viruses may be attenuated using the principles of

evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...

via

serial passage Serial passage is the process of growing bacteria or a virus in iterations. For instance, a virus may be grown in one environment, and then a portion of that virus population can be removed and put into a new environment. This process is repeated ...

of the virus through a foreign

host A host is a person responsible for guests at an event or for providing hospitality during it. Host may also refer to: Places * Host, Pennsylvania, a village in Berks County People *Jim Host (born 1937), American businessman * Michel Host ...

species, such as: *

Tissue culture Tissue culture is the growth of tissues or cells in an artificial medium separate from the parent organism. This technique is also called micropropagation. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, su ...

* Embryonated

eggs Humans and human ancestors have scavenged and eaten animal eggs for millions of years. Humans in Southeast Asia had domesticated chickens and harvested their eggs for food by 1,500 BCE. The most widely consumed eggs are those of fowl, especial ...

(often chicken) * Live animals The initial virus population is applied to a foreign host. Through natural

genetic variability Genetic variability is either the presence of, or the generation of, genetic differences. It is defined as "the formation of individuals differing in genotype, or the presence of genotypically different individuals, in contrast to environmentally i ...

or induced

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

, a small percentage of the viral particles should have the capacity to infect the new host. These strains will continue to evolve within the new host and the virus will gradually lose its efficacy in the original host, due to lack of

selection pressure Any cause that reduces or increases reproductive success in a portion of a population potentially exerts evolutionary pressure, selective pressure or selection pressure, driving natural selection. It is a quantitative description of the amount of ...

. This process is known as "passage" in which the virus becomes so well adapted to the foreign host that it is no longer harmful to the subject that is to receive the vaccine. This makes it easier for the host immune system to eliminate the agent and create the immunological memory cells which will likely protect the patient if they are infected with a similar version of the virus in "the wild". Viruses may also be attenuated via reverse genetics. Attenuation by genetics is also used in the production of

oncolytic virus An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic vir ...

es.

Attenuated bacteria

Bacteria is typically attenuated by passage, similar to the method used in viruses. Gene knockout guided by reverse genetics is also used.

Administration

Attenuated vaccines can be administered in a variety of ways: * Injections: ** Subcutaneous (e.g. measles, mumps and rubella vaccine,

varicella vaccine Varicella vaccine, also known as chickenpox vaccine, is a vaccine that protects against chickenpox. One dose of vaccine prevents 95% of moderate disease and 100% of severe disease. Two doses of vaccine are more effective than one. If given to t ...

yellow fever vaccine Yellow fever vaccine is a vaccine that protects against yellow fever. Yellow fever is a viral infection that occurs in Africa and South America. Most people begin to develop immunity within ten days of vaccination and 99 percent are protected ...

) ** Intradermal (e.g.

tuberculosis vaccine Tuberculosis (TB) vaccines are vaccinations intended for the prevention of tuberculosis. Immunotherapy as a defence against TB was first proposed in 1890 by Robert Koch.Prabowo, S. et al. "Targeting multidrug-resistant tuberculosis (MDR-TB) by ...

smallpox vaccine The smallpox vaccine is the first vaccine to be developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox ...

) * Mucosal: ** Nasal (e.g.

live attenuated influenza vaccine Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that is recommended for the prevention of influenza. It is an attenuated vaccine, unlike most influenza vaccines, which are inactivated vaccin ...

) ** Oral (e.g.

oral polio vaccine Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all child ...

, recombinant live attenuated

cholera vaccine Cholera vaccines are vaccines that are effective at preventing cholera. For the first six months after vaccination they provide about 85percent protection, which decreases to 50percent or 62percent during the first year. After two years the level ...

, oral typhoid vaccine, oral rotavirus vaccine) Oral vaccines or subcutaneous/intramuscular injection are for individuals older than 12 months. Live attenuated vaccines, with the exception of the rotavirus vaccine given at 6 weeks, is not indicated for infants younger than 9 months.

Mechanism

Vaccines function by encouraging the creation of cells, such as

CD8+ A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...

and

CD4+ T lymphocytes The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...

, or molecules, such as antibodies, that are specific to the

. The cells and molecules can either prevent or reduce infection by killing infected cells or by producing

interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...

s. The specific effectors evoked can be different based on the vaccine. Live attenuated vaccines tend to help with the production of CD8+ cytotoxic T lymphocytes and T-dependent antibody responses. A vaccine is only effective for as long as the body maintains a population of these cells. Attenuated vaccines are “weakened” version of pathogens (virus or bacteria). They are modified so that it cannot cause harm or disease in the body but are still able to activate the immune system. This type of vaccine works by activating both the cellular and humoral immune responses of the adaptive immune system. When a person receives an oral or injection of the vaccine, B cells, which help make antibodies, are activated in two ways: T cell-dependent and T-cell independent. In T-cell dependent activation of B cells, B cells first recognize and present the antigen on MHCII receptors. T-cells can then recognize this presentation and bind to the B cell, resulting in clonal proliferation. This also helps IgM and plasma cells production as well as immunoglobulin switching. On the other hand, T-cell independent activation of B cells is due to non-protein antigens. This can lead to production of IgM antibodies. Being able to produce a B-cell response as well as memory killer T cells is a key feature of attenuated virus vaccines that help induce a potent immunity.

Safety

Live-attenuated vaccines are safe and stimulate a strong and effective immune response that is long-lasting. Given pathogens are attenuated, it is extremely rare for pathogens to revert to their pathogenic form and subsequently cause disease. Additionally, within the five WHO-recommended live attenuated vaccines (tuberculosis, oral polio, measles, rotavirus, and yellow fever), severe adverse reactions are extremely rare. Individuals with severely compromised immune systems (e.g., HIV-infection,

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

combined immunodeficiencies Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity. This category includes conditions su ...

) typically should not receive live-attenuated vaccines as they may not be able to produce an adequate and safe immune response. Household contacts of immunodeficient individuals are still able to receive most attenuated vaccines since there is no increased risk of infection transmission, with the exception being the oral polio vaccine. As precaution, live-attenuated vaccines are not typically administered during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

. This is due to the risk of transmission of virus between mother and fetus. In particular, the varicella and

s have been shown to have adverse effects on fetuses and nursing babies. Some live attenuated vaccines have additional common, mild adverse effects due to their administration route. For example, the

is given nasally and is associated with nasal congestion. Compared to

s, live-attenuated vaccines are more prone to immunization errors as they must be kept under strict conditions during the

cold chain A cold chain is a low temperature-controlled supply chain network. An unbroken cold chain is an uninterrupted series of refrigerated production, storage and distribution activities, along with associated equipment and logistics, which maintain qu ...

and carefully prepared (e.g., during reconstitution).

History

The history of

development started with the creation of the

Edward Jenner Edward Jenner, (17 May 1749 – 26 January 1823) was a British physician and scientist who pioneered the concept of vaccines, and created the smallpox vaccine, the world's first vaccine. The terms ''vaccine'' and ''vaccination'' are derived f ...

in the late 18th century. Jenner discovered that inoculating a human with an animal pox virus would grant immunity against

smallpox Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...

, a disease considered to be one of the most devastating in human history. Although the original

is sometimes considered to be an attenuated vaccine due to its live nature, it was not strictly-speaking attenuated since it was not derived directly from smallpox. Instead, it was based on the related and milder

cowpox Cowpox is an infectious disease caused by the ''cowpox virus'' (CPXV). It presents with large blisters in the skin, a fever and swollen glands, historically typically following contact with an infected cow, though in the last several decades more ...

disease. The discovery that diseases could be artificially attenuated came in the late 19th century when Louis Pasteur was able to derive an attenuated strain of

chicken cholera Fowl cholera is also called avian cholera, avian pasteurellosis, avian hemorrhagic septicemia. Abraham b. It is the most common pasteurellosis of poultry. As the causative agent is ''Pasteurella multocida'', it is considered to be a zoonosis. Adu ...

. Pasteur applied this knowledge to develop an attenuated

anthrax vaccine Anthrax vaccines are vaccines to prevent the livestock and human disease anthrax, caused by the bacterium ''Bacillus anthracis''. They have had a prominent place in the history of medicine, from Pasteur's pioneering 19th-century work with cattle ...

and demonstrating its effectiveness in a public experiment. The first

rabies vaccine The rabies vaccine is a vaccine used to prevent rabies. There are a number of rabies vaccines available that are both safe and effective. They can be used to prevent rabies before, and, for a period of time, after exposure to the rabies virus, ...

was subsequently produced by Pasteur and

Emile Roux Emil or Emile may refer to: Literature *'' Emile, or On Education'' (1762), a treatise on education by Jean-Jacques Rousseau * ''Émile'' (novel) (1827), an autobiographical novel based on Émile de Girardin's early life *'' Emil and the Detecti ...

by growing the virus in rabbits and drying the affected nervous tissue. The technique of cultivating a virus repeatedly in artificial media and isolating less

virulent Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

strains was pioneered in the early 20th century by

Albert Calmette Léon Charles Albert Calmette ForMemRS (12 July 1863 – 29 October 1933) was a French physician, bacteriologist and immunologist, and an important officer of the Pasteur Institute. He discovered the Bacillus Calmette-Guérin, an attenuated for ...

and

Camille Guérin Jean-Marie Camille Guérin (; 22 December 1872 – 9 June 1961) was a French veterinarian, bacteriologist and immunologist who, together with Albert Calmette, developed the Bacillus Calmette-Guérin (BCG), a vaccine for immunization against tube ...

who developed an attenuated

called the

BCG vaccine Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended ...

. This technique was later used by several teams when developing the vaccine for

, first by Sellards and Laigret, and then by Theiler and Smith. The vaccine developed by Theiler and Smith proved to be hugely successful and helped establish recommended practices and regulations for many other vaccines. These include the growth of viruses in primary tissue culture (e.g., chick embryos), as opposed to animals, and the use of the seed stock system which uses the original attenuated viruses as opposed to derived viruses (done to reduce variance in vaccine development and decrease the chance of adverse effects). The middle of the 20th century saw the work of many prominent virologists including Sabin, Hilleman, and

Enders Enders or Ender's may refer to: Literature and film * ''Ender's Game'' (series), a series of science fiction books by Orson Scott Card, also known as the Ender saga ** '' Ender's Game'', a 1985 military science fiction novel ** '' Ender's Shadow ...

, and the introduction of several successful attenuated vaccines, such as those against

polio Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe s ...

, measles, mumps, and rubella.

Advantages and disadvantages

Advantages

* Accurately imitate natural infections. * Are effective at evoking both strong

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

and cell-mediated immune reactions. * Can elicit long-lasting or life-long immunity. * Often only one or two doses are required. * Quick immunity onset. * Cost-effective (compared to some other health interventions). * Can have strong beneficial non-specific effects.

Disadvantages

* In rare cases, particularly when there is inadequate vaccination of the population, natural

s during

viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome an ...

, or interference by related viruses, can cause an attenuated virus to revert to its

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

form or mutate to a new

strain Strain may refer to: Science and technology * Strain (biology), variants of plants, viruses or bacteria; or an inbred animal used for experimental purposes * Strain (chemistry), a chemical stress of a molecule * Strain (injury), an injury to a mu ...

, potentially resulting in the new virus being infectious or pathogenic. * Often not recommended for severely

immunocompromised Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

patients due to the risk of potential complications. * Live strains typically require advanced maintenance, such as refrigeration and fresh media, making transport to remote areas difficult and costly.

List of attenuated vaccines

Currently in-use

For many of the pathogens listed below there are many vaccines, the list below simply indicates that there are one (or more) attenuated vaccines for that particular pathogen, not that all vaccines for that pathogen are attenuated.

Bacterial vaccines

Anthrax vaccine Anthrax vaccines are vaccines to prevent the livestock and human disease anthrax, caused by the bacterium ''Bacillus anthracis''. They have had a prominent place in the history of medicine, from Pasteur's pioneering 19th-century work with cattle ...

Cholera vaccine Cholera vaccines are vaccines that are effective at preventing cholera. For the first six months after vaccination they provide about 85percent protection, which decreases to 50percent or 62percent during the first year. After two years the level ...

Plague vaccine Plague vaccine is a vaccine used against ''Yersinia pestis'' to prevent the plague. Inactivated bacterial vaccines have been used since 1890 but are less effective against the pneumonic plague, so live, attenuated vaccines and recombinant protein ...

* Salmonella vaccine *

Tuberculosis vaccine Tuberculosis (TB) vaccines are vaccinations intended for the prevention of tuberculosis. Immunotherapy as a defence against TB was first proposed in 1890 by Robert Koch.Prabowo, S. et al. "Targeting multidrug-resistant tuberculosis (MDR-TB) by ...

Typhoid vaccine Typhoid vaccines are vaccines that prevent typhoid fever. Several types are widely available: typhoid conjugate vaccine (TCV), Ty21a (a live oral vaccine) and Vi capsular polysaccharide vaccine (ViPS) (an injectable subunit vaccine). They are ab ...

Viral vaccines

* Live attenuated influenza vaccine (LAIV) *

Japanese encephalitis vaccine Japanese encephalitis vaccine is a vaccine that protects against Japanese encephalitis. The vaccines are more than 90% effective. The duration of protection with the vaccine is not clear but its effectiveness appears to decrease over time. Doses ...

Measles vaccine Measles vaccine protects against becoming infected with measles. Nearly all of those who do not develop immunity after a single dose develop it after a second dose. When rate of vaccination within a population is greater than 92%, outbreaks o ...

Mumps vaccine Mumps vaccines are vaccines which prevent mumps. When given to a majority of the population they decrease complications at the population level. Effectiveness when 90% of a population is vaccinated is estimated at 85%. Two doses are required fo ...

* Measles and rubella (MR) vaccine * Measles, mumps, and rubella (MMR) vaccine * Measles, mumps, rubella and varicella (MMRV) vaccine *

Polio vaccine Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all chi ...

Rotavirus vaccine Rotavirus vaccine is a vaccine used to protect against rotavirus infections, which are the leading cause of severe diarrhea among young children. The vaccines prevent 15–34% of severe diarrhea in the developing world and 37–96% of s ...

Rubella vaccine Rubella vaccine is a vaccine used to prevent rubella. Effectiveness begins about two weeks after a single dose and around 95% of people become immune. Countries with high rates of immunization no longer see cases of rubella or congenital rubell ...

Smallpox vaccine The smallpox vaccine is the first vaccine to be developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox ...

Varicella vaccine Varicella vaccine, also known as chickenpox vaccine, is a vaccine that protects against chickenpox. One dose of vaccine prevents 95% of moderate disease and 100% of severe disease. Two doses of vaccine are more effective than one. If given to t ...

Yellow fever vaccine Yellow fever vaccine is a vaccine that protects against yellow fever. Yellow fever is a viral infection that occurs in Africa and South America. Most people begin to develop immunity within ten days of vaccination and 99 percent are protected ...

* Zoster/shingles vaccine

In development

Bacterial vaccines

Enterotoxigenic Escherichia coli Enterotoxigenic ''Escherichia coli'' (ETEC) is a type of ''Escherichia coli'' and one of the leading bacterial causes of diarrhea in the developing world, as well as the most common cause of travelers' diarrhea. Insufficient data exist, but conser ...

vaccine

Viral vaccines

Tick-borne encephalitis vaccine Tick-borne encephalitis vaccine is a vaccine used to prevent tick-borne encephalitis (TBE). The disease is most common in Central and Eastern Europe, and Northern Asia. More than 87% of people who receive the vaccine develop immunity. It is not ...

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...

References

External links

Global Polio Eradication Initiative: Advantages and Disadvantages of Vaccine Types

at the website of the US

Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

{{Authority control Vaccination Virology